UA53628C2 - 5-о-deozaminyl -6-о-methylerythronolide a derivatives, a process for preparation thereof, intermediate compounds and a process for erythromycine derivatives preparation - Google Patents

Abstract

Compounds of formula (I), wherein OR1, OR2 and OR3 are hydroxyl radicals protected so as to form easily cleavable radicals, are useful for preparing antibiotic products.

Description

Description of the invention

This invention belongs to new derivatives of 5-O-desosaminyl-6-O-methylerythronolide A, the method of their preparation and their 2 application for obtaining biologically active products.

The object of the present invention are compounds of the formula L/: r V and Li n zay r! Oh, it's okay, " etc., drinking nanny

G 0 o "ov z o "7 -

ОЕ 2 сч that in which: o or Ki is an alkyl radical containing up to 8 carbon atoms, substituted by one or more alkyl radicals containing up to 8 carbon atoms, or one or more aryl radicals containing up to 14 carbon atoms, so z o or KK. is an aryl radical containing up to 14 carbon atoms, and which can be substituted by one or more alkyl, alnenyl or alkynyl radicals containing up to 6 carbon atoms, alkoxy or alkylthio containing up to 8 carbon atoms, nitro, C3 or by one or more halogen, He or CC atoms. is a radical:

E Ge)

And" yu p - sh- and ШШШШ

About Y

Ba « du in which -o

Ka is an alkyl or alkoxy radical containing up to 8 carbon atoms, c K is an alkyl radical containing up to 8 carbon atoms and which can be substituted by a heteroatom, :z" Ko is a hydrogen atom or an alkyl radical containing up to 8 carbon atoms;

EK" and Kz are the same or different and represent a trialkylsilyl radical, in which the alkyl radical contains up to 8 15 carbon atoms, in 1 | and. o radical - -06--KB." radical o -6--K4,

Fr. Y with 50 VE e o in which Ka, KB, Kye and Ku represent an alkyl radical containing up to 8 carbon atoms, or an aralkyl radical containing up to 8 carbon atoms and which can be replaced by one or by several of the substituents listed above for Ku.

In the defined compounds according to the invention: the radical alkyl, alkenyl or alkynyl preferably means the radical methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or o cyclohexyl, ime) halogen preferably means fluorine or chlorine, or bromine, the aryl radical mainly means the phenyl radical or the naphthyl radical, 60 the aralkyl radical means the radical gadinal /СеНв/-/СНо/а, where a is an integer from 1 to b, for example , number 1, 2, C or 4; an aralkyl radical can be, for example, a benzyl radical, optionally substituted, or a trityl radical, an alkoxy radical preferably means a methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tertiary butyloxy, n-pentyloxy, isopentyloxy, secondary pentyloxy radical , tertiary pentyloxy, 65 neopentyloxy, n-hexyloxy, secondary hexyloxy, tertiary hexyloxy, the alkylthio radical can take the same values by replacing the oxygen atom with a sulfur atom, for example:

methylthio, ethylthio. In addition, the sulfur atom can be oxidized and represent, for example, methylsulfinyl, methylsulfonyl.

Compounds according to the invention can be used to obtain compounds of formulas /L//; o We are here

KO e oi pen" sews t tane (3 pe" 3 7 "y o ok o z

K-02 in which 7 represents a hydrogen atom or a protective group, such as a carboxylic acid residue containing up to 8 carbon atoms, a trialkylsilyl radical or tertiary butyl. with

The compounds of the formula /L/I/ are described and claimed in the application for. European patent No. 0 487 411 as intermediate products used, in particular, to obtain antibiotic products.

More specifically, the object of the present invention is the compounds of the formula //, in which Ki is the radical: her. so k-0-0-- p

F

Ko (ze) in which Ka, K and Ko have the above values, in particular, compounds in which Ka, K and Ko represent a methyl radical, as well as compounds of the formula // in which Ko and Kz both represent a trialkylsilyl radical, in particular, compounds in which K" and Kz represent the trimethylsilyl radical.

A more specific object of the invention is a compound of the formula /L/, the preparation of which is given below in the experimental part. "

The object of the present invention is also a method of obtaining the compounds of the formula // described above, which differs from that in that the compound of the formula Li

K ey 1 Sh o no p (e)) you ok ptn z 50 is inn pitna ee ev (in p 0 h so char 0 oi o i ia (F; that g 60 is subjected to the action of an oxime blocking agent in position 9 to obtain compound of the formula LII/: b5

LIY seam,

N g rai no he and" he too

Gas schi i TO TER I 70 - I o te 0 Ov V ra i-

ОН in which K/ has the above value, which is subjected to the action of a hydroxyl blocking agent in position З and/or 2", to obtain a compound of the formula Л/ЛМ/: ; М : р В ' с

Ye pi o no o

And On tep so and I - Me. pennetnamaninny in the village

Hm) t Ge)

MORE about OV. at 7 and Is) heh

ОЕ 2 « - с in which Ку, Ко and Кз have the values indicated above, which is subjected to the action of the hydroxyl methylating agent in position "» 6 to obtain the corresponding compound of the formula /L/. " The compound of the formula Li/, which is used as a starting product, represents the well-known product is described by the authors Mapiiea and Soi|., in the journal U. Med. Spet., 17/9/, 953 - 956 /1974/.

In a preferred embodiment of the method according to the invention: the oxime in position 9 is protected in the form of a ketal, thioketal; c groups of 3-onH and 2'-OH are blocked by trimethylsilyl groups; methylation is carried out using methyl iodide in the presence of a base, for example, potassium hydroxide, me) sodium hydroxide, a hydride, such as sodium hydride, tertiary butylate of an alkali metal, such as for example

He 50 of potassium tertiary butylate, or in the presence of 1,5-diazabicyclo|4,3,O|non-5-ene or 1,8-diazabicyclo|5,4,Fundec-7-ene. The object of the present invention are new chemical products of the formula L/LI/ and the formula /M/ obtained by carrying out the method according to the invention. More specifically, the invention belongs to the products of formula LII/ and formula LM/, the method of obtaining which is given in the experimental part.

The invention also relates to the use of compounds of the formula /L/, which consists in the fact that the compound of the formula /L/

GF! are subjected to the following operations: liberation of the oxime in position 9, liberation of hydroxyl in position C and 2, protection of hydroxyl in position 2". In particular, this invention relates to the application, which consists in the fact that the compound of the formula /L/ is subjected to the action of formic acid in in the presence of sodium bisulfite or sodium metabisulfite to obtain directly the compound of the formula ///: b5

E

(o; and - oNe

BUT

.

We about

PI

(8) koke 7 och pi tk . zv, pinnnnaninaninn y (ee) and o 7 sch ot (Se) o o o r so

I

IC c) 02 in which 7 represents a protective group, such as a carboxylic acid residue containing up to 8 carbon atoms, C7C 70 or a trialkylsilyl, tertiary butyl or triphenylmethyl radical. c The invention also relates to an application that differs in that. the compound of the formula // is subjected to the action of an agent "for the release of hydroxyl in positions C and 2". to obtain a compound of the formula L/LI/:

We eat that V, os ID ay

Me. ng |: Still) ke - NI I ni ze o ke pkhanaanya ya A NI NI o toi o y (F, g ime) sya 60 in which K. has the value indicated above, which is exposed to the action of the protective agent of group OH in position 2, to obtain a compound of the formula /L/P/: b5

LP rai i Y

What is this: he av those ch

ГНы 70 pc pe, I panny anniz Go)

what about her t-

And 02 in which K/ has the value indicated above, and 7 means the protective group defined above, which is subjected to the action of a 9-oxo group-releasing agent to obtain the corresponding compound of the formula /L/I/: b My ! with

M o co o g . And point with ate, with" (so) she ate, we V!

And o - p

F t o on 2 room apartment

From I iv) then « 70 in which 2 has the above-mentioned value. c The following examples illustrate the invention without limiting it. "from Example 1 9-O-/1-methoxy-1-methylethyl/oxime 3-O-de/2,6-dideokei-3-C-methyl-3-O-methyl-alpha-i!-ribo-hexopyranosyl /-2", sl 15 of 3-O-bis/trimethylsilyl/6-O-methylerythromycin.

Stage A: 9-O-/1-Methoxy-1-methylethyl/oxime (4) 3-O-de/2,-6-dideoxy-3-C-methyl-3-O-methyl-alpha-i-ribo -hexopyranosyl/-erythromycin.

F Stir for half an hour at room temperature 8.14 g of 9-oxime 3-O-de/2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-y-ribo-hexapyranosyl/erythromycin, 81, 5 ml of methylene chloride, 9.65 ml of 2-methoxypropene and 2.44 g of 9895 pyridinium chloride. VOml of a saturated solution of MansSo»z is added, and the solution is moved for 3 minutes. Decant the organic phase, which is washed with 50 ml of salt water.

The aqueous phases are re-extracted with 500 ml of СНоСі". The organic phase is dried over NaCl and the solvent is evaporated under reduced pressure. They get 9 of the target product. The output is 98.5905.

Analysis results: 99 NMR /SO Siz, ZOOMHCC/

HF) 0.84 l/: SNi-CH"; 1.07 /d/ - 1.09 /d/ - 1.23 /d/ -1.26 /d/x2 : SNUZ-SN; 2.25 /s/: M/Me/"; 2.48 /m/ : N'z; 2.64 /dk/: No; t 2.72 /cli: Nio; 3.22 /s/: ОМе; - 3.25: N'"; 3.51 /d/: Nv; 3.58 /dl/: Nz; 3.68 /sl/ : No4; - 3.50 /m/: N'v; - 3.62 /m/ : No -»

IS; 4.41 /d/: H'/; 5.23 /dd/ : Niz; 2.36 - 4.48 - 5.58; H are mobile. in Stage B and 9-0-/1-methoxy-1-methylethyl/oxime 3-O-de-/2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-i-ribo-hexopyranosyl /-2",3-O-bis/trimethylsilyl/oerythromycin

Mix a mixture of 6.62 g of the product obtained at the previous stage, bbml of SNoxSi", 2.95 ml

M-trimethylsilylimidazole, 1.7 ml of trimethylsilyl chloride for 45 minutes at ambient temperature.

Add 50 ml of a saturated solution of MansSoO»z. The organic phase is decanted, which is washed with 40 ml of sodium chloride. The organic phase is dried over Ma»5O) and the solvent is evaporated under reduced pressure. They get 7.5 g of the target product. Output: 92,990.

Analysis results:

NMR /CO Siz, ZOOMHz/ 0.12 - 0.16 OTM5; 0.84 l/: SNZ-SN"; 1.16 /х2/ - 1.38 - 1.45 - 1.47 - 1.00 -1.25: SNU-SN; 2.23 /s/ : M/Me/"; 2.47

Im/ : N'z; 2.71 /m/ : H" and No; 3.16 /dd/: H'"; 3.22 /s/ : ОМе; 3.45 /m/ and New; 3.58 /d/ : No; 3.66: On -» E;. 3.66 /s/: H..4; 3.98 /dl/ : Nouz;. 4.2 /dd/: H'/; 5.14 /dd/: Niz3; 1.90 /s/ - 3.10 - 4.44: ON.

Stage (F : 9-0-/1-methoxy-1-methylethyl/oxime 3-O-de-/2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-i-ribo-hexopyranosyl /-2",3-O-bis/trimethylsilyl/ 70 8-O-methylerythroiacin.

Mix 1.24 g of the product obtained in the previous stage, 8.7 ml of a mixture of dimethyl sulfoxide/tetrahydrofuran 1/1, 190 μl of methyl iodide, 161 mg of powdered potassium hydroxide 90905 for 2 hours at ambient temperature. . After decantation and re-extraction in AsOE, the organic phase is filtered with 5 ml of water, dried over Na»5O), and the filtrate is concentrated under reduced pressure. 1.2 g of the target product is obtained. Output: 9590.

Analysis results:

NMR /CO Siz, ZOOMHz/ possible structure; localize at 0.11 and 0.20 groups of 5iMez; 0.84 /l/; SNU-SN»o; 0.95 /d/ - 0.97 /d/ -1.14 20. /B/- 1.17 Id/ x 2: SNUZ-SN; 1.18 - 1.935 - 1.40 - 1.48: SNU-SN; 2.22 /s/ : M/Me/"; 2.46 /m/: N'z; 2.61 /cl/: Nero; 2.72

Idk/; Not"; 3.01 /s/; OMe; 3.13 /dd/: New; 3.22 /s/ OhMe chain; 3.45 /m/: N'v; - 3.70: At -» E; - 3.68 /m/ : 2Н /Н»з, Нб/; 3.79 /sl//1Н -» N.I. 4.24 /d/: NU; 5.15 /dd/: N/z; 3.29 and 4.52: ON.

Application 1 0:00 2'-O-acetyl-3-O-de/2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-i -ribo-hexopyranosyl/ 6-O-methylerythromycin. Ge

Stage A: 3-O-de/2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-Y! -ribo-hexopyranosyl/ 6-O-methylerythromycin. at

A mixture of 51 mg of the product from example 1, 5 ml of ethanol/water 1/1, 42 mg of sodium bisulfite, 115 μl of formic acid is stirred for half an hour at a reflux temperature. After cooling to ambient temperature, add 5 ml of a saturated solution of ManSoO»z. The mixture is stirred for 5 minutes, then extracted twice with ASOEI. The extracted phases are washed with bml. o saturated solution of Masi. The organic phase is dried over NaClO) and the solvent is evaporated in a vacuum. 180 mg of the target product are obtained after chromatography on silicon dioxide with the eluent: ASOEI 95/Meon Z/TEA 2. The yield cm 48905. (Se)

Analysis results;

NMR /SO Siz, 250MHz/ o

The spectrum is identical! given from the literature: 5.17 /d/: H4z; 4.38 /d/: H' 3.93 /sl/ : H are mobile; 3.85 /s/: No; 368 yuyu /s/ : Nv; 3.54 - 3.62 /m/ : Nz, N'v; 3.24 /m/ : H'"; 2.98 /s/ : Ohme; 2.25 /s/ : M/Me/»2; 1.37 -1.31 - 1.27 - 1.25 - 1.21 - 1.18 - 1.14 - 1.11: CHNaZ-CH; 0.83 l/: СNi-СН".

Stage B: 2-O-acetyl-3-O-de/2,6-dideoxy-3-C-methyl-3-C-methyl-alpha-i! -ribo-hexopyranosyl/ « 6-O-methylerythromycin.

The product obtained at the previous stage is subjected to the action of acetic anhydride and the target product is obtained. - s Application 2:00 2'-O-acetyl-3-O-de/2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-i -ribo-hexopyranosyl/ a 6-O- methylerythromycin. "» Stage A : 9-0-/1-methoxy-1-methylethyl/oxime 3-O-de/2,-6-dideoxy-3-C-methyl-3-O-methyl-alpha-i!-ribo -hexopyranosyl/6-O-methylerythromycin.

To a mixture of 2.75 g of the product from example 1 and 5.5 ml of tetrahydrofuran, add 8.25 ml of a one-molar solution of tetrabutylammonium fluoride in tetrahydrofuran quickly and at ambient temperature, then stir for 45 minutes. Then a mixture of 15 ml of ethyl acetate and 15 ml of ice water is added. After decantation, the organic phase is re-extracted with 3 ml of water. Add 0.82 ml of concentrated (o) ammonium hydroxide to the aqueous phase. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with 50 mL of a saturated aqueous solution of sodium chloride, then dried over sodium sulfate and the solvent is evaporated under reduced pressure. 2.17 g of the target product are obtained. Output: 95.7905.

IR e) Analysis results:

NMR /CO Siz, ZOOMHz/ 0.84 l/ : СNi-СН»; 0.97 /d/ - 1.10 /d/ - 1.18 /d/ - 1.24 /d/ - 1.26 /d/ : SNUZ-SN; 1.20 - 1.40 /х 2/ - 148: SNUZ-S; 2.26 Is/: M/Me/»; 2.13 /cl/ : Well; 2.48 /m/ : N'z; 2.66: But and No; 2.98 /s/ x ОМе in position 6; 3.22 /s/ : Ohme o chain;. 7 3.26 NN"; - 3.54: Nz and H'5; 3.68 /s/ - 3.83 /d/: H5 and H.44; - 3.73 /m/ At -» E; 4.38 /d/; N'/; 5.23 /dd/: Niz.

Stage B: 9-O-/1-methoxy-1-methylethyl/oxime) 2-O-acetyl-3-O-de/2,6-dideoxy-3-C-methyl-3-O-methyl-alpha - and -ribo-hexopyranosyl/ 6-O-methylerctromycin.

A mixture of 2.17 g of the product prepared in the previous stage, 22 ml of CH2Cl3, 39 0 ml of acetic anhydride is stirred for one and a half hours at ambient temperature. Add 22 ml of saturated sodium bicarbonate solution. Wash the organic phase with 1 Oml of salt water. The aqueous phases are re-extracted using СНоСи»о. The organic phase is dried over sodium sulfate, then the solvent is evaporated under reduced pressure. The resulting residue is treated with 4.25 ml of isopropyl ether, then 14.9 ml of heptane. After stirring for 5 minutes, the residue is dehydrated, then washed with heptane. After 65 drying, 1.72 g of the target product /colorless crystals/ are obtained. T.pl. - 2007. Output 74.7965.

Analysis results:

NMR /CO Siz, ZOOMHz/ 0.83 //: СNi-СН»; 0.92 /d/ - 0.97 /d/ - 1.17 /d/ - 1.28 /d/ - 1.30 /d/ : SNaiZ-SN; 1.18 -1.29-1.40-1.47: SNU-S; 2.06 /s/ : OAs; 2.26 /s/ : M/Me/"; 2.59 /kl/ : But; 2.69 /m/ : N'z and N»e; 2.95 /s/ x OMe in position 6; 3.22 /с/ : ОМе lace; with 3.47: NU; Not the N'5; 3.73 /d/: Nv; 3.79 /sl/ : No4;. 4.60 /d/ : H'; 4.77 /dd/ : No; 5.23 /dd/ : Niz; 1.72 /d/ - 3.32 - 4.63: H are mobile.

Stage (F: 2-O-acetyl-3-O-de/2,6-dideoxy-3-C-methyl-3-O-methyl-adpha-i-ribo-hexopyranosyl/ 6-O-methylerythromycin.

A mixture of 180 mg of the product obtained at the previous stage, 1.8 ml of ethanol/water 1/1, 23 μl of 9895 formic acid 7/0, 180 mg of sodium bisulfite is stirred for 3 and a half hours at a reflux temperature. Cool to room temperature and add 1.8 ml of saturated sodium bicarbonate solution. Then, after 3 minutes of stirring, extract 2 times СНоСиИ». The organic phase is washed with 2 ml of saturated aqueous Masi solution. The organic phase is dried over sodium sulfate, the solvent is evaporated under reduced pressure. After purification of the residue by chromatography on silicon dioxide, /5 eluting with ethyl acetate, which contains 295 tetrahydrofuran, 4 Zmg of the target product are obtained. Exit 2790.

Analysis results:

IR: -ON - 3626 cm"! /max/ 3500 cm"! -0 1735 cm"! 1689 cm"! with

Claims (1)

Formula of the invention (8) 1. Derivatives of 5-O-desosaminyl-6-Y-methylerythronolide A of the general formula (1): 7, WHAT HE! I () « OVz I o o) ee s M z ov, ' 1 in which Ki is a radical of the formula: OO , Va Ge) v-o-: mo b t v so s in which Ka is an alkyl or alkoxy containing up to 8 carbon atoms, Kb is an alkyl containing up to 8 carbon atoms and which may be substituted by a heteroatom, o Es is a hydrogen atom or an alkyl containing up to 8 carbon atoms, PE" and Kz are the same and are trialkylsilyl , in which alkyl contains up to 8 carbon atoms. ko 2. Compounds according to claim 1 of formula (I), in which Ka, K and Ko are methyl. Z. Compounds according to claim 1 of formula (I), in which K» and Kz are trimethylsilyl. bo 4. The compound according to claim 1 of formula (), which is 9-0-(1-methoxy-1-methylethyl)oxime 3-O-de(2,6-dideoxy-3-C-methyl-3-O-methyl - 5: -I -ribohexopyranosyl)-2'0, 3-O-bis(trimethylsilyl)-6-O-methylerythromycin. 5. The method of obtaining derivatives of 5-O-desosaminyl-6-O-methylerythronolide A of the general formula (I) according to any of clauses 1-4, which differs in that the compound of the formula (I): b5 "On (I) M Shk 5. but - they are OH and o podo o ono Yo IR OH is treated with an oxime-protecting agent in position 9 to give the compound of formula (I): ov. in which Ku has the value specified in claim 1, riy Ї Kk no on chi on 1, sem Um "i, KU "vi, shi o 2 I chi y (n0) o on se) 7 sch M (Se) y n o , which is subjected to the action of an agent that protects the hydroxy group in position З and in position 27, to obtain a compound of the formula (IM): in which Ku, Ko" and Kz have the values indicated in claim 1, ов, " M | - with KO;" but on m on that o U "i, . KU '. t, o | pap F that (M) (c) "v, ih) 7-o so Sk zv Ov, (F) which is treated with an agent that methylates the hydroxy group in the b position, with the receipt of the corresponding GI compound of formula (1). 6. The method according to point 5, which is characterized by the fact that the methylation of the compound of the formula (IM) is carried out with the help of methyl iodide in the presence of a base. 7. Derivatives of erythromycin of the general formula (I): b5 Ov, in which Ku has the value indicated in claim 1, as intermediate compounds ,/ І m no on m ОН '", Um p, 7170 (U p, "I (y 1. a, ХХО shchi schu ! (IN) o "on - M on, for obtaining compounds according to claims 1-4. 8. Derivatives of erythromycin of the general formula (IM): OB, in which K., Ko and Kz have the values indicated in claim 1, as 4 M s U o no on KO Ge p! t, o m "p, pe, cm p, ',. (Se) s ' (M) iy / o ot. | with IS c) M Ov, « ' 3 with intermediate compounds for obtaining compounds according to claims 1-4. and 9. The compound according to claim 7, which is: -methyl-7-I-ribohexopyranosyl) erythromycin; 10. The compound according to claim 8, which is: 1 9-0-(1-methoxy-1-methylethyl)oxime /3-O-de(2,6-dideoxy-3-C-methyl-3-O- methyl-?:-|-ribohexopyranosyl)-2'0, 3-O-bis(trimethylsilyl)erythromycin. about : : ; ; . 11. The method of obtaining erythromycin derivatives of the general formula (MI): (o) in which 7 is a protective group, such as a carboxylic acid residue from 50 Ki IR e) " no OME KO (inc! i, GF) KO shcha p, yuyu | p , o s y (M) 60 o - M b 02 , acids containing up to 8 carbon atoms, trialkylsilyl, tert-butyl and triphenylmethyl, which is characterized by the fact that the compound of formula (I) is subjected to the following transformations: - the oxime in position 9 is released, - the hydroxy group is released in position C and 2, - the hydroxy group is protected in position 2". 12. The method according to point 11, which differs in that the compound of the formula (I) is treated with formic acid in the presence of sodium bisulfite or sodium metabisulfite, with the preparation of the compound of the formula (M): which is subjected to the action of an agent that protects the hydroxy group in KO) OMe m on ',, m Kl m" t, t, ' i o "on 9 Ge) - MU on s ' (o) position 2", with obtaining the compound of formula (MI). 13. The method according to clause 11, which is characterized by the fact that the compound of the formula (I) is subjected to the action of an agent that releases the hydroxy group in the position З and in the position 2", to obtain the compound of the formula (MI): ov in which Ku has the specified in claim 1 meaning, so r 1 and sch KO that so SO NO OME yu KO on t, Hm t "a g f, and that ch schi I and (MI) Z s 9) "on . o - p » ih . Gu on , (95) which is subjected to the action of an agent that protects the hydroxy group in position 2", to obtain a compound of the formula (MP): (22) with 50 IR f) Ф) име) 60 b5 ов in which Ki has the above value and 7 is protective Y KO no OME Ko on SCHO m po, te « sho y (MI) (o) "on y 2 1 group, and which is subjected to the action of an agent that releases the 9-oxo group, to obtain a compound of the formula (MI). Official Bulletin " Industrial property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M 2, 15.02.2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 1 (95) (22) of 50 p F) name) 60 b5